Apolipoprotein A-IV Stabilizes Glucose Metabolism in Diabetic Mouse Model

This enhancement involved cAMP (3'-5'-cyclic adenosine monophosphate) at a location distant from the point entry of calcium ions into insulin-producing beta cells.

Genetically engineered “knockout” of apoA-IV resulted in compromised insulin secretion and impaired glucose tolerance compared with wild type mice. Challenging mice lacking apoAI-V with a high-fat diet led to fasting hyperglycemia and more severe glucose intolerance associated with defective insulin secretion than occurred in wild type mice. Administration of exogenous apoA-IV to the “knockout” mice improved glucose tolerance by enhancing insulin secretion in mice fed either chow or a high-fat diet.

Injection of exogenous apoA-IV decreased blood glucose levels and stimulated a transient increase in insulin secretion in KKAy diabetic mice.

Senior author Dr. Patrick Tso, professor of pathology and laboratory medicine at the University of Cincinnati, said, “ApoA-IV behaves similar to an incretin - a gastrointestinal hormone causing an increased release of insulin after eating to combat the onset of elevated blood glucose. Two well-known incretins that have been used in the development of existing diabetes medications include gastric inhibitory peptide (GIP) and glucagon-like peptide-1 (GLP-1).”

"The problem with both of these incretins is that they are short-lived - lasting only for minutes - and are quickly inactivated by an enzyme,” said Dr. Tso. “They have also been linked to hypoglycemia, or low blood sugar, when administered when the body has a low glucose concentration. The challenge is to find something safer with a longer half-life.”

With its long (seven to eight hour) half-life apoA-IV may be a suitable therapeutic target for the regulation of glucose-stimulated insulin secretion and treatment of diabetes.

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